Figure 7.

Long-term MCL-1 Inhibition Causes Defects in Functionality and Mitochondrial Morphology of hiPSC-CMs

(A–E) Chronic inhibition of MCL-1, but not BCL-2, results in cardiac activity defects. hiPSC-CMs were treated every 2 days with DMSO, 100 nM S63845 (orange), 100 nM ABT-199 (green), or both inhibitors (magenta) for 14 days. MEA recordings were taken 2 h following each treatment for 5 min, and results were normalized to baseline recording for each respective well, followed by normalization to DMSO (gray dotted line). Results of recordings for spike amplitude mean (A), spike slope mean (B), conduction velocity mean (C), max delay mean (D), and propagation consistency (E) are shown. p values show significance as follows: ∗ = DMSO versus S63845, † = DMSO versus Combination, # = S63845 versus ABT-199, ‡ = S63845 versus Combination, • = ABT-199 versus Combination. One symbol indicates p < 0.05, two symbols indicate p < 0.01, three symbols indicate p < 0.001, and four symbols indicate p < 0.0001. p values were determined by two-way ANOVA. Graphs represent mean ± SEM.

(F–I) Mitochondria and F-actin were imaged at the end of the treatment paradigm in Figures 6A–6E. Representative images are shown of cells treated with DMSO (F), 100 nM S63845 (G), 100 nM ABT-199 (H), and 100 nM S63845 + 100 nM ABT-199 (Combination) (I). Scale: 10 μm. See also Figure S6.